The present invention is generally directed to the treatment of viral infections, and more particularly to a method and compound for the prophylaxis or treatment of an immunodeficiency condition, such as acquired immunodeficiency syndrome (AIDS).
AIDS has been reported to be first identified in 1981 among homosexual men and intravenous drug users in New York and California. Shortly after its detection in the United States, evidence of AIDS epidemics grew among heterosexual men, women, and children in sub-Saharan Africa. AIDS quickly developed into a worldwide epidemic, affecting virtually every nation. It is reported that by 2000, an estimated 34.7 million adults and 1.4 million children worldwide, had HIV infection or AIDS. The World Health Organization (WHO), a specialized agency of the United Nations (UN), estimates that from 1981 to the end of 2000 about 21.8 million people died as a result of AIDS. More than 4.3 million of those who died were children under the age of 15.
In the United States, about 40,000 new HIV infections occur each year. More than thirty percent of the infections occur in women, and sixty percent occur in ethnic minorities. About 800,000 to 900,000 U.S. residents were infected with HIV, and about 300,000 people were living with full-blown AIDS, in 2000. In Canada, about 4,200 new HIV infections occur each year. About twenty-three percent of these infections occur in women. About 40,000 Canadians were living with HIV infection or full-blown AIDS in 2000.
The incidence of new cases of HIV infections and AIDS deaths has significantly decreased in Canada and the United States since 1995. This decrease is attributed to the availability of new drug treatments and public health programs that target people most at risk for infection. But while the overall rate of HIV infection seems to be on a downturn, certain populations appear to be at greater risk for the disease. In the United States in 1987, Caucasians accounted for sixty percent of AIDS cases, and blacks and Hispanics only thirty-nine percent. But by 2000 the trend had reversed: thirty-eight percent of new cases were diagnosed in Caucasians and sixty-one percent in blacks and Hispanics. Likewise the number of female AIDS patients in the United States has increased significantly in recent years, from seven percent of all AIDS cases in 1985 to thirty percent in 2000. In the United States, African American and Hispanic women accounted for eighty-two percent of AIDS cases among women in 2000.
In western Europe the first cases of AIDS were detected in the early 1980s, and by the late 1990s, at least 30,000 new HIV infections occurred each year. In 2000, more than 540,000 western Europeans were HIV positive, and twenty percent of these cases were women. Before the dissolution of the Union of Soviet Socialist Republics (USSR) in 1991, eastern Europe reported few HIV cases. But since 1995, HIV infection has spread rapidly in cities of several eastern European countries, including Ukraine, Belarus, and Moldova. The WHO estimates that the total number of HIV infections in this region may have risen from less than 30,000 in 1995 to more than 700,000 in 2000.
While cases of AIDS have been reported in every nation of the world, the disease affects some countries more than others. More than ninety-five percent of all HIV-infected people live in the developing world. In these areas, the disease has sapped the populations of young men and women who form the foundation of the labor force. Most die while in the peak of their reproductive years. Moreover, the epidemic has overwhelmed health-care systems, increased the number of orphans, and caused life expectancy rates to plummet. These problems have reached crisis proportions in some parts of the world already burdened by war, political upheaval, or unrelenting poverty.
Nowhere is this better demonstrated than in sub-Saharan Africa, where the number of AIDS cases far exceeds that of all other geographic regions. Of the estimated 16,000 HIV infections that occur each day worldwide, 7,500 of them occur in sub-Saharan Africa. More than seventy percent of all people infected with HIV live in this region. In some countries in the southern part of the continent, including Botswana, Namibia, Swaziland, and Zimbabwe, as much as twenty-five percent of the population has HIV infection or AIDS.
In Asia, the rates of HIV infection remain low relative to many other areas, but the number of reported cases markedly increased in recent years. Health officials fear the virus will affect more people if it spreads through China and India, the world's two most populous countries. For example, 1992 marked the first reported cases of HIV infection in India. By the end of 1999 nearly 4 million adults in India were HIV positive. These cases were mostly confined to 10 of the nation's states, while the remaining 24 states reported low infection rates. HIV infection in India initially was reported primarily in sex workers, but it has quickly spread to the general population in less than five years. Health officials fear that without public education programs, cases of HIV infection will escalate over the next decade, causing the AIDS epidemic in India to dwarf the problems seen in sub-Saharan Africa.
In 2002, the Chinese government reported that China had 850,000 HIV-positive people in a population of more than 1 billion. However, public health experts are concerned by the fast-rising number of new infections among intravenous drug users who share infected needles. In 2000, HIV prevalence among intravenous drug users ranged from forty-four percent to eighty-five percent in selected communities of drug users in both Yunnan, in southern China, and Xinjiang, in northwestern China. The incidence of HIV infection will likely be exacerbated by the growing sex industry in China. Surveys indicate that there are as many as 4 million sex workers in China. Of these, five out of ten never use a condom to protect themselves or their clients from HIV infection or other sexually transmitted infections. In rural areas of China, the incidence of HIV infection is rising because many poverty-stricken people regularly sell their blood. The people who buy the blood use unsterile methods to draw blood, including reusing contaminated needles, which can spread HIV infection.
In Latin America and the Caribbean, region nearly 1.8 million people have been diagnosed with HIV infection or AIDS, twice the incidence in the United States and Canada. In Mexico, 150,000 people have been diagnosed with HIV infection or AIDS, and the disease is the third leading cause of death in men aged 20 to 34. Honduras, which accounts for less than a fifth of the population in Central America, reports more than half of the AIDS cases in that region. In the state of Sao Paolo, Brazil, AIDS has been the leading cause of death among women aged 20 to 34 since 1992.
Historically, the recognized treatment for HIV-1 infection is nucleoside analogs, inhibitors of HIV-1 reverse transcriptase (RT). Intervention with these antiretroviral agents has led to a decline in the number of reported AIDS cases and has been shown to decrease morbidity and mortality associated with advanced AIDS. Prolonged treatment with these reverse transcriptase inhibitors eventually leads to the emergence of viral strains resistant to their antiviral effects. Recently, inhibitors of HIV-1 protease have emerged as a new class of HIV-1 chemotherapy. HIV-1 protease is an essential enzyme for viral infectivity and replication. Protease inhibitors have exhibited greater potency against HIV-1 in vitro than nucleoside analogs targeting HIV-1 RT. Inhibition of HIV-1 protease disrupts the creation of mature, infectious virus particles from chronically infected cells. This enzyme has become a viable target for therapeutic intervention and a candidate for combination therapy.
Knowledge of the structure of the HIV-1 protease also has led to the development of novel inhibitors, such as saquinovir, ritonavir, indinivir and nelfinavir. NNRTIs (non-nucleoside reverse transcriptase inhibitors) have recently gained an increasingly important role in the therapy of HIV infection. Several NNRTIs have proceeded onto clinical development (i.e., tivirapine, loviride, MKC-422, HBY-097, DMP 266). Nevirapine and delaviridine have already been authorized for clinical use. Every step in the life cycle of HIV-1 replication is a potential target for drug development.
Unfortunately, however, the single targeted approach as stated above, has only been able to target RT or PR enzymes. As a result, this approach has favored the virus natural selection to evade drug therapy by mutating at a single or few amino acid sequences. According to a CDC report (December 2001), 75% mortality rate in HIV-1 patients is co-related to drug resistant HIV variants. The search for new antiretroviral effective drug against HIV-1 resistant variants has dramatically increased.
Many of the antiretroviral drugs currently used in chemotherapy either are derived directly from natural products, or are synthetics based on a natural product model. The rationale behind the inclusion of deoxynucleoside as a natural based antiviral drugs originated in a series of publications dating back as early as 1950, wherein the discovery and isolation of thymine pentofuranoside from the air-dried sponges (cryptotethia crypta) of the Bahamas was reported. A significant number of nucleosides were made with regular bases but modified sugars, or both acyclic and cyclic derivatives, including AZT and acyclovir. The natural spongy-derived product led to the first generation, and subsequent second—third generations of nucleosides (AZT, DDI,DDC,D4T,3TC) antivirals specific inhibitors of HIV-1 RT.
A number of non-nucleoside agents (NNRTIs) have been discovered from natural products that inhibit RT allosterically. NNRTIs have considerable structural diversity but share certain common characteristics in their inhibitory profiles. Among NNRTIs isolated from natural products include: calanoid A from calophylum langirum; Triterpines from Maporonea African a. There are publications on natural HIV integrase inhibitors from the marine ascidian alkaloids, the lamellarin.
The role of HIV protease in the production of functionally infectious particle has been described as a critical process for retrovirus as well as HIV replication. The natural product, Pepstatin A, is a metabolite of streptomycin testaceus and Streptomyces argentolus var. toyonakensis was shown to inhibit HIV-1 Protease enzyme. The key strategy used in the development of the current HIV-1 protease inhibitors was to substitute the scissile P1-P1 amide bond by a nonhydrozable isoster with tetrahedral geometry; the designs were guided by assays and based on substrate specificity. It eventually led to the optimization of peptidomimetric lead structure and the development of novel class of protease inhibitors including indinvir, Saqunovir, nelfinavir and retinovir.
In Ethiopia, there are currently more than 3 million adults and close to 1 million children infected with HIV-1. The rate of HIV-1 vertical and horizontal transmission has drastically increased over the years. More than 50% of the nation's available hospital beds are over crowded with HIV-1 patients, and 99.9% of the HIV-1 patients cannot afford the commercially available antiretroviral drugs. Even for those who can afford it (<0.1%) there is no HIV-1 staging or managing infrastructure to evaluate therapeutic indices. The national health status is in a state of emergency that could cripple the national economy and decimate the younger generations. Unless immediate therapeutic and behavioral interventions are expedited, the exponential rate of HIV-1 growth and related morbidity could easily reach 6 million by the year 2005. This is a deadly reality that Ethiopians, Ethiopian HIV-1 experts, and the world at large are currently confronted with.
In order to provide therapeutic intervention to 400,000 AIDS infected patients with the commercially available drugs, the country of Ethiopia alone will have to spend close to 2 billion dollars a year. This figure does not include other concomitant drugs needed for TB, abdominal fungus, pneumonia, toxic effects caused by drugs and monthly patient evaluation for therapeutic index and HIV-1 dose response assessments. This approach is simply way beyond the GNP of Ethiopia.
The other serious problem arising from importing and prescribing non-HHART (highly active retrovirus therapy) drug treatments in Ethiopia is the creation of fertile environment for the emergence of highly virulent, resistant viruses. More than 75% of AIDS therapeutic failure is caused by resistance viruses. A centralized data bank and HIV-1 management team is crucial to monitor the success or failure of antiretroviral therapy. Salvage therapy with the commercial drugs, triple or quadruple combination is essential to reach effective clinical diagnostic therapeutic index. This again could bankrupt the economy of Ethiopia.
In view of the drawbacks associated with conventional remedies and the growing worldwide concern for the AIDS epidemic, there is a need for a remedy which is inexpensive, less toxic, potent, and easily available. In this regard, the inventors of the present invention believe that the compound or antiviral agent of the invention, H2K1001(90l or 90i), would be a perfect alternative since it is less costly, highly potent, easy to deliver to AIDS patients, and highly active against resistant viruses. In addition, the compound of the invention is a simple multi-charged molecule that could be manufactured at low cost. Consequently, the cost of the drug would be affordable to the majority of AIDS patients in Ethiopia and other developing countries.